Abstract MH94320 seeks 3 years of renewed support to test the effects of the NMDA antagonist, memantine (MEM), on auditory processing in patients with schizophrenia (SZ). Studies in FY 1-4 produced the surprising and unprecedented findings that a single pill of MEM (20 mg) significantly enhanced (made ?more normal?) 3 measures of aberrant early auditory information processing (EAIP) in SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma auditory steady-state response (ASSR). Based on structural equation modeling evidence that EAIP is a root cause of functional impairment in SZ, a drug-induced improvement in EAIP is a compelling neurobiological signal that MEM is accessing brain mechanisms that ultimately will provide a pathway to therapeutics. However, acute gains in EAIP are insufficient to enhance neurocognition in SZ. This renewal application tests the impact of MEM on functional measures of auditory processing fidelity (APF) and auditory learning in SZ patients and matched healthy subjects (HS), to identify ?intermediate phenotypes?, bridging immediate MEM-enhanced EAIP with eventual gains in neurocognition and function. Such findings would implicate mechanisms connecting neurophysiological measures of EAIP to the neurocognitive and functional outcomes that they generate, and would identify candidate biomarkers predicting a therapeutic response to MEM, paired with Targeted Cognitive Training (TCT), in future clinical trials. While current medications for SZ do not significantly enhance functional outcome, some forms of auditory-based TCT effectively reduce symptoms and improve function in SZ. One premise of this application is that benefits of TCT in SZ will be enhanced by drugs that increase specific cognitive abilities, including auditory processing. While the clinical impact of MEM in SZ is controversial, no studies have tried to utilize MEM's positive effects on EAIP to augment the benefits of TCT. We propose to test a mechanistic rationale for a future trial of ?Pharmacologic Augmentation of Cognitive Training? (PACT) with MEM, in which MEM- enhanced EAIP improves neurocognition and function in SZ patients via gains in APF and/or auditory learning. In 3 years, MH94320 will test the prediction that MEM (20 mg p.o.) will acutely enhance functional measures of APF and learning as well as EAIP in 41 SZ patients and 41 HS, via a double-blind, placebo- controlled cross-over design (Aim 1). Regional sources of MEM-enhanced EAIP will be localized. Predictors of MEM sensitivity will be assessed, including baseline performance, and specific SNPs in glutamate receptor genes previously associated with MEM sensitivity. Path Analyses will determine if MEM-enhanced EAIP leads to improved APF/learning, thus establishing a specific pathway to therapeutic enhancement of cognition and function (Aims 2-3). Findings will guide future efforts by explicating mechanisms by which MEM-enhanced EAIP produces gains in neurocognition and function, and by identifying ?personalized? biomarkers of MEM sensitivity as well as candidate physiological signals of target engagement for a future R61/R33 application.